Steroid-sparing Therapy Research Articles

Autoimmune diseases: MIF as a therapeutic target

Importance of the field: Autoimmune inflammatory diseases occur commonly in developed countries. The treatment of these diseases is usually non-curative and is aimed at suppressing inflammatory end-organ damage. Macrophage migration inhibitory factor (MIF) is a multipotent cytokine that has been implicated in the pathogenesis of numerous autoimmune inflammatory disorders. The selective targeting of MIF with either anti-MIF antibody or specific MIF antagonists may offer new therapeutic avenues for these diseases.Areas covered in this review: Our aim is to discuss MIF-directed therapies as a novel therapeutic approach. The review covers literature from the past 10 years.What the reader will gain: MIF inhibition has been shown to be efficacious in many experimental and pre-clinical studies of autoimmune inflammatory diseases. The close regulatory relationship between MIF and glucocorticoids makes therapeutic antagonism of MIF a potential steroid-sparing therapy in patients with refractory autoimmune diseases.Take home message: We expect that MIF antagonism by either small-molecule- or antibody-based approaches will find wide application in the treatment of autoimmune inflammatory diseases. Such therapy also may be informed by the MIF genotype of affected patients.

Cicatrising conjunctivitis with anti-basement membrane autoantibodies in ectodermal dysplasia

Aims:To report circulating and mucosa-deposited anti-basement membrane zone autoantibodies in a series of six ectodermal dysplasia patients with severe bilateral cicatrising conjunctivitis and blindness due to both corneal disease and...

Final analysis of MM-014: Single-agent lenalidomide in patients with relapsed and refractory multiple myeloma

8524 Background: Lenalidomide (Len) in combination with high-dose dexamethasone (Dex) is approved for previously treated patients (pts) with multiple myeloma (MM). This study determined the efficacy and safety of Len monotherapy in pts with relapsed/refractory MM. Methods: Len monotherapy (30 mg qd) was given to pts with relapsed/refractory MM in a single-arm, open-label multi-center study. Len was administered daily on days 1–21 every 28 days. Concomitant Dex was not permitted. No anticoagulation prophylaxis was recommended. Treatment was continued as tolerated until disease progression. Response was assessed every month using modified EBMT criteria and toxicity using NCI-CTCv3. Results: All 222 enrolled pts had received ≥2 prior anti-MM therapies, including bortezomib (43%), thalidomide (80%), and SCT (45%); 46% had ≥4 prior therapies with a mean time from diagnosis of 4 years. At database lock, 64 pts (29%) had received treatment for >9 months. For the intention-to-treat population (n=222), the overall response (OR: CR+PR) was 26%. An additional 66% of the pts experienced stable disease (SD). OR for the efficacy-evaluable population (n=184) was 32% and 68% experienced SD. By study completion, 151 pts (69%) had progressed with a median time-to-progression (TTP) of 5.4 months. Median progression-free survival (PFS) was 4.7 months, and median overall survival (OS) was 1.9 years with 41% of pts alive after 3 years. Median duration of response was 13 months (median FU: 14 months). The most common grade 3/4 lab toxicities were neutropenia (60%), thrombocytopenia (39%) and anemia (20%). Only 4% of pts developed febrile neutropenia and DVT; no grade 3/4 peripheral neuropathy was seen. Conclusions: The encouraging OR, duration of response, TTP, PFS, and OS seen in this study demonstrate that Len monotherapy at a dose of 30 mg once daily (3 wks on, 1 wk off) is effective, durable, and well tolerated steroid-sparing therapy for heavily pretreated pts with relapsed/refractory MM. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Celgene Celgene, Millennium Celgene Celgene, Millennium Celgene

Obesity following kidney transplantation and steroid avoidance immunosuppression

Obesity is an important co-morbidity within end-stage renal disease (ESRD) and renal transplant populations. Previous studies have suggested that chronic corticosteroids result in increased body weight post-transplant. With the recent adoption of steroid-sparing immunosuppressive strategies, we evaluated the effect of these strategies on body mass index (BMI) after renal transplantation. We examined 95 renal transplant recipients enrolled in National Institutes of Health clinical transplant trials over the past three yr who received either lymphocyte depletion-based steroid sparing or traditional immunosuppressive therapy that included steroids for maintenance immunosuppression. Recipients were overweight prior to transplant and no significant differences existed in pre-transplant BMI among treatment groups. Regardless of therapy, BMI increased post-transplant in all recipients. The BMI increase consisted of an average weight gain of 5.01 +/- 7.12 kg (mean, SD) post-transplant. Additionally, in a number of recipients placed on maintenance steroids, subsequent withdrawal at a mean of 100 d post-transplant had no impact on weight gain. Thus, body weight and BMI increase following kidney transplantation, even in the absence of steroids. Thus, patients gain weight after renal transplantation regardless of the treatment strategy. Steroid avoidance alone does not reduce risk factors associated with obesity in our patient population.

Biliary Complications after Duct‐to‐duct Biliary Reconstruction in Living‐donor Liver Transplantation: Causes and Treatment

In living-donor liver transplantation (LDLT), biliary complications are recognized as a significant cause of post-transplantation morbidity. Eighty patients who underwent LDLT with duct-to-duct biliary reconstruction at Hiroshima University Hospital were enrolled in this study. The mean follow-up was 24 months (range, 3-72 months). Eighteen patients underwent the basiliximab-based immunosuppressive therapy, and 62 patients underwent non-basiliximab-based immunosuppressive therapy. The development of biliary complications after LDLT was retrospectively analyzed. Biliary complications were initially treated by endoscopic or radiological modalities. Biliary leakages and strictures occurred in 12 (15%) and 20 (25%) of the 80 patients, respectively. Stepwise multivariate analysis demonstrated bile leakage to be an independent risk factor for the development of biliary stricture (p = 0.001) and basiliximab-based immunosuppressive therapy to be an independent protective factor for postoperative biliary leakage (p = 0.005). The 1-week total doses of steroids were significantly lower in the basiliximab-based immunosuppressive regimes (mean dose: 573 mg) than in the non-basiliximab-based ones (mean dose: 1,121 mg) (p = 0.01). All patients with biliary leakage were successfully treated with endoscopic or radiological modalities, except one patient who was treated by surgical treatment. Endoscopic or radiological modalities were successful as primary treatment modalities in 12 (60%) of 20 patients with biliary strictures. Lastly, six patients were treated surgically with long-term success, except for one patient with chronic cholangitis who died after 16 months. Steroid-sparing basiliximab-based immunosuppressive therapy reduced the incidence of biliary leakage, and biliary leakage was the independent factor for biliary stricture. The non-surgical and surgical treatments for biliary complications were satisfactory.

EBV-associated lymphoproliferative disorder of CNS associated with the use of mycophenolate mofetil

Epstein-Barr virus (EBV)-associated lymphoid proliferations are a well-recognized complication of congenital or acquired systemic immunosuppression. The CNS is a frequent site for development of such lymphoid proliferations. We describe the clinical, imaging, and pathologic observations of a CNS disorder histologically similar to posttransplantation lymphoproliferative disorder that occurred in four patients with autoimmune disease treated with mycophenolate mofetil (MM). Two patients had polymorphous lymphoplasmacytic infiltration of brain parenchyma, and two had monomorphous infiltrations consistent with diffuse large B-cell lymphoma. In situ hybridization for EBV-encoded RNA was positive in all four patients. All patients improved after MM withdrawal and the use of rituximab. Because of a favorable toxicity profile, MM is now being used as steroid-sparing immunomodulatory therapy in autoimmune disorders. Based on our experience presented herein, we recommend caution in patient selection for MM and strict surveillance of those patients with autoimmune disorders who receive MM.

The role of macrophage migration inhibitory factor in the inflammatory immune response and rheumatoid arthritis

Rheumatoid arthritis (RA) is a debilitating disease of unknown etiology. Although the pathogenesis of RA is multifactorial, the contribution of cytokines is undoubtedly pivotal in the progression of the inflammatory process. One cytokine gaining recognition for its importance in inflammation is macrophage migration inhibitory factor (MIF). Initially described as a biological activity, a broad range of functions of MIF has emerged including induction of proinflammatory mediators as well as demonstrated roles in both innate and adaptive immunity. In RA, increased MIF levels have been demonstrated in serum, synovial fluid and tissue with the latter correlating with disease activity. In vitro, MIF induces production of key proinflammatory genes operative in arthritis, including IL-1, TNF, IL-6, IL-8, COX-2, PLA2, and MMPs. In addition, MIF regulates proliferation and apoptosis via direct effects on the tumor suppressor protein p53 implicating a role for MIF in synovial hyperplasia. In vivo, MIF antagonism or MIF deficiency result in decreased disease severity in animal models of RA further confirming a role for MIF in joint inflammation. Interestingly, MIF is induced by glucocorticoids and MIF in turn antagonises glucocorticoid effects. This unique relationship presents antagonism of MIF as a potentially effective steroid-sparing therapy.

PP2. LONG-TERM FOLLOW-UP OF POLYMYALGIA RHEUMATICA PATIENTS TREATED WITH METHOTREXATE AND STEROIDS

Objectives A series of patients with polymyalgia rheumatica (PMR) who received the steroid-sparing combination therapy, prednisone and methotrexate (MTX), underwent a long-term follow-up study at fi ve years to investigate possible reductions of steroid-related side effects. Additional end-points were the number of patients still in need of steroid treatment, the cumulative steroid dose, and the number of fl are-ups of PMR. Patients and methods

Corticosteroids: Options in the era of steroid-sparing therapy

Topical corticosteroids remain the most commonly used topical treatments for inflammatory dermatoses, including psoriasis and atopic dermatitis. Topical corticosteroids are available in a variety of vehicles-creams, ointments, lotions, gels, and, more recently, foam. The vehicle used can substantially affect the individual agent's clinical action, potency, and acceptability to the patient. Moreover, some vehicles are better suited for specific body areas. Selection of the appropriate product should be determined by area of usage, physician experience, cost, and patient preference, particularly regarding vehicle. Although topical corticosteroids are associated with several side effects, including skin atrophy, telangiectases, purpura, and striae formation, appropriate usage can minimize these occurrences. Judicious use includes short-term, appropriate application as initial monotherapy or in combination strategies with other therapeutic agents that ideally possess complementing mechanisms of action. Examples include pulsing with high-potency topical corticosteroids and combination regimens with other topical agents such as topical calcineurin inhibitors, calcipotriene, or tazarotene. Appropriate education of patients and caregivers alike will facilitate the optimal use of these medications.

Immunomodulatory Therapy for Ocular Inflammatory Disease: A Basic Manual and Review of the Literature

Corticosteroids are used as first-line treatment for many ocular inflammatory conditions. The risk of adverse effects, however, necessitates conversion to steroid-sparing immunomodulatory therapy (IMT) for disease that is recurrent, chronic, or poorly responsive to treatment. Combination drug treatments with multiple agent ‘recipes’ are also considered. Immunomodulatory agents include the broad categories of antimetabolites (azathioprine, methotrexate, mycophenolate mofetil), alkylating agents (cyclophosphamide, chlorambucil), T-cell inhibitors (cyclosporine, tacrolimus), and cytokines (interferon alfa). This article reviews and summarizes the evidence for IMT agent use in the treatment of various forms of ocular inflammation.

Montelukast improves asthma control in asthmatic children maintained on inhaled corticosteroids

Because of potential toxicities of inhaled corticosteroid (ICS) use in pediatric asthma, alternative or steroid-sparing therapy is desirable. There are no previous studies evaluating montelukast's steroid-sparing effects in children with asthma. To evaluate whether (1) montelukast as add-on therapy improves asthma symptom control and (2) montelukast provides steroid-sparing effects in children with asthma treated with low to moderate doses of ICS therapy. In a double-blind, placebo-controlled trial, 36 children ages 6 to 14 years with symptomatic asthma maintained on a stable low to moderate dose of ICSs were randomly assigned to receive montelukast or matching placebo for 24 weeks after a run-in period of 2 weeks (period I). During the trial, subjects kept daily asthma diary cards and monthly spirometry was performed. After a 4 week add-on period (period II), the subjects completed a 20-week (period III) ICS tapering period based on a predetermined protocol. In period II, the difference in the number of rescue-free days was significantly higher in the montelukast group (P = 0.0001), and the number of rescue-free days per week was also significantly higher in montelukast-treated subjects compared with placebo subjects (P = 0.002). In period III, the percentage reduction in ICS dose was not significant between montelukast and placebo (P = 0.10), but the montelukast group experienced an average 17% decrease in ICS dose and the control group experienced an average 64% increase in ICS dose. Montelukast treatment significantly increased the number of rescue-free days in symptomatic children with asthma.

Unihemispheric cerebral vasculitis mimicking Rasmussen's encephalitis.

A previously healthy 10-year-old boy presented with right-sided headache and focal motor seizures characterized by left facial twitching. Examination revealed a left hemiparesis. CT scan demonstrated a large, right frontoparietal mass containing calcification. Biopsy showed changes consistent with cerebral vasculitis involving the cortex, white matter, and leptomeningeal vessels. Despite treatment with dexamethasone 3 mg/day for 6 weeks, the patient’s condition deteriorated, with increasing left-sided weakness and a new left hemianopia. On re-investigation, inflammatory markers, autoantibody profile, and neurotropic virus screen were negative. CSF examination revealed intrathecal synthesis of oligoclonal bands but was otherwise normal. A cerebral angiogram showed the right middle cerebral artery and its branches to be of smaller caliber than the left. In view of the re-activation of the cerebral vasculitis, treatment with 2 mg/kg/day prednisolone was given for 3 months. His condition stabilized, and azathioprine was introduced as a steroid-sparing immunosuppressive therapy. Despite occasional focal seizures, he remained stable for the next decade, at which time the azathioprine therapy was withdrawn. Serial MRI was …

Early Australian experience with infliximab, a chimeric antibody against tumour necrosis factor-alpha, in the treatment of Crohn's disease: is its efficacy augmented by steroid-sparing immunosuppressive therapy? The Infliximab User Group.

Tumour necrosis factor-alpha (TNF-alpha) plays an important role in the pathology of Crohn's disease. Infliximab, a chimeric antibody against TNF-alpha, has been shown in controlled clinical trials to be effective in two-thirds of patients with refractory or fistulating Crohn's disease. The factors that determine a clinical response in some patients but not others are unknown. To document the early Australian experience with infliximab treatment for Crohn's disease and to identify factors that may determine a beneficial clinical response. Gastroenterologists known to have used infliximab for Crohn's disease according to a compassionate use protocol were asked to complete a spreadsheet that included demographic information, Crohn's disease site, severity, other medical or surgical treatments and a global clinical assessment of Crohn's disease outcome, judged by participating physicians as complete and sustained (remission for the duration of the study), complete but unsustained (remission at 4 weeks but not for the whole study) or partial clinical improvement (sustained or unsustained). Fifty-seven patients were able to be evaluated, with a median follow-up time of 16.4 (4-70) weeks, including 23 patients with fistulae. There were 21 adverse events, including four serious events. Fifty-one patients (89%) had a positive clinical response for a median duration (range) of 11 (2-70) weeks. Thirty patients (52%) had a remission at 4 weeks, 10 of whom had remission for longer than 12 weeks. Forty-two per cent of fistulae closed. Sustained remission (P = 0.065), remission at 4 weeks (P = 0.033) and a positive clinical response of any sort (P = 0.004) were more likely in patients on immunosuppressive therapy, despite there being more smokers in this group. This review of the first Australian experience with infliximab corroborates the reported speed and efficacy of this treatment for Crohn's disease. The excellent response appears enhanced by the concomitant use of conventional steroid-sparing immunosuppressive therapy.

Pathogenesis, prevention and treatment of transplant-associated osteoporosis

A reduction in bone mass is observed in a high percentage of patients following organ or marrow transplantation, with the prevalence of osteopenia or osteoporosis reported to be as high as 80%. Between 4 and 65% of transplant recipients will experience an osteoporosis-related fracture and the likelihood of such a serious outcome is dependent on pre-existing disease and immunosuppressive therapy. End-stage pulmonary disease is commonly associated with a reduction in BMD; chronic liver disease with osteomalacia and osteoporosis; and renal patients are often recognised to have osteodystrophy, osteopaenia or osteoporosis at the time of transplantation. Post-transplant glucocorticoid therapy plays a major role in the further reduction in bone mass observed in these patients. Glucocorticoids have several effects deleterious to the skeleton, transiently increasing bone resorption then subsequently inhibiting both osteoclast and osteoblast activity. They also interfere with calcium, vitamin D and PTH metabolism. The additional role of other immunosuppressant treatments in bone loss is less clear but there is some evidence to suggest that cyclosporin A (CsA) and tacrolimus (FK506) result in high bone turnover osteopenia. CsA can also result in hypogonadism when used in high doses and hypomagnesaemia which can contribute to a reduction in bone mass. Comparative studies in renal transplant patients have suggested that CsA monotherapy has less of an effect on BMD than combination therapy with glucocorticoids. Newer immunosuppressants such as rapamycin are believed to have minimal effects on bone metabolism compared to CsA or FK506. Although some variability exists in the studies reporting bone related outcomes following transplant, current evidence suggests that the cumulative dose of glucocorticoid, male gender, increasing age and development of an early menopause as a result of treatment are the factors associated with severe bone disease. Since the greatest loss of bone is observed in the first 3-6 months following transplant, coincident with glucocorticoid therapy, strategies to prevent bone loss should be directed at the peri-operative period. Reduction in the use of glucocorticoids by using steroid-sparing combination therapy has been effective and in cardiac transplant patients the use of vitamin D or its analogues in combination with calcium has also proved beneficial. Early reports of the use of intravenous pamidronate are encouraging with improved BMD and significant reductions in fractures reported.

Plasmapheresis as a steroid saving procedure in bullous pemphigoid.

Bullous pemphigoid is an immunobullous disease affecting predominantly older patients. In severe cases, high-dose corticosteroids and/or other immunosuppressants are often needed long term to control the disease. These can be associated with serious side-effects in this patient population. Objective To evaluate the benefit of plasmapheresis as a steroid saving agent in a cohort of 10 patients. Plasmapheresis was effective as a steroid saving therapy. All patients went into remission with a lower daily dosage of oral prednisone at 3 and 6 months postplasmapheresis. Two patients had side-effects from therapy that, while significant, did not interfere with long-term improvement in their disease. Eight patients had circulating immunoglobulin G (IgG) antibodies reactive with bullous pemphigoid antigen 1, and three of these had circulating antibodies reactive with bullous pemphigoid antigen 2 on Western immunoblot. Plasmapheresis was an effective steroid sparing therapy in these patients. Due to its high cost and potential morbidity, plasmapheresis should not be recommended as routine therapy for bullous pemphigoid, but it is a useful adjunct in resistant cases.

PHARMACOLOGIC VARIABILITY OF EVERY OTHER DAY (QOD) GLUCOCORTICOID THERAPY IN RENAL TRANSPLANT RECIPIENTS (RTR)

287 In order to minimize chronic adverse effects, the use of the lowest effective doses of corticosteroids (prednisone or methylprednisolone-MEPN) are currently recommended in the combination immunosuppressive protocols prescribed in RTR. Therefore, more RTR are receiving steroid-sparing therapy that employ every other day (QOD) glucocorticoid regimens based upon empiric dosing titration. To examine total glucocorticoid exposure during QOD dosing, seven (4 males; 3 females) stable RTR (ranging from 7 months to 7 years post-transplant) stabilized on QOD glucocorticoid doses were evaluated. Patients (mean serum creatinine: 1.4 ± 0.2 mg/dl) were administered their respective oral MEPN dose (dose range: 4 to 14 mg QOD) by intravenous infusion at 8 AM of study. Blood samples were collected at time 0 (0800) and for 24 hours following and analyzed with HPLC for MEPN and cortisol. Significant interpatient variability was noted in the clearance (CL) of MEPN that ranged from 180 to 574 ml/hr/kg. The corresponding half-life(t1/2) ranged from 2.0 to 3.7 h. A defined 24 h cortisol profile was noted an all patients. Cortisol concentrations (mean cortisol at time 0:127± 50 ng/ml) declined concurrent with the serum MEPN. Cortisol rebounded from a mean nadir concentration of 9.2 ± 4.4 ng/ml to 24 hour mean cortisol concentration of 104 ± 39 ng/ml. The total cortisol AUC ranged from 541 to 1438 ng•h/ml and was not correlated with dose or CL of MEPN. No significant correlation was noted between these pharmacologic parameters and patient demographics. These results indicate that pronounced interpatient variability in the pharmacokinetics of MEPN exists during QOD therapy. In addition, the cortisol response during QOD therapy suggests unpredictable recovery rates of the HPA axis. The variation in total glucocorticoid exposure during empiric tapering to QOD therapy suggest that a more objective approach is needed to maintain adequate immunosuppression while also attempting to avoid chronic steroid toxicity. These variations in the MEPN clearance and cortisol recovery may explain why aggressive steroid tapering is complicated by rejection episodes that occur in an unpredictable manner.

PHARMACOLOGIC VARIABILITY OF EVERY OTHER DAY (QOD) GLUCOCORTICOID THERAPY IN RENAL TRANSPLANT RECIPIENTS (RTR)

287 In order to minimize chronic adverse effects, the use of the lowest effective doses of corticosteroids (prednisone or methylprednisolone-MEPN) are currently recommended in the combination immunosuppressive protocols prescribed in RTR. Therefore, more RTR are receiving steroid-sparing therapy that employ every other day (QOD) glucocorticoid regimens based upon empiric dosing titration. To examine total glucocorticoid exposure during QOD dosing, seven (4 males; 3 females) stable RTR (ranging from 7 months to 7 years post-transplant) stabilized on QOD glucocorticoid doses were evaluated. Patients (mean serum creatinine: 1.4 ± 0.2 mg/dl) were administered their respective oral MEPN dose (dose range: 4 to 14 mg QOD) by intravenous infusion at 8 AM of study. Blood samples were collected at time 0 (0800) and for 24 hours following and analyzed with HPLC for MEPN and cortisol. Significant interpatient variability was noted in the clearance (CL) of MEPN that ranged from 180 to 574 ml/hr/kg. The corresponding half-life(t½) ranged from 2.0 to 3.7 h. A defined 24 h cortisol profile was noted an all patients. Cortisol concentrations (mean cortisol at time 0:127 ± 50 ng/ml) declined concurrent with the serum MEPN. Cortisol rebounded from a mean nadir concentration of 9.2 ± 4.4 ng/ml to 24 hour mean cortisol concentration of 104 ± 39 ng/ml. The total cortisol AUC ranged from 541 to 1438 ng·h/ml and was not correlated with dose or CL of MEPN. No significant correlation was noted between these pharmacologic parameters and patient demographics. These results indicate that pronounced interpatient variability in the pharmacokinetics of MEPN exists during QOD therapy. In addition, the cortisol response during QOD therapy suggests unpredictable recovery rates of the HPA axis. The variation in total glucocorticoid exposure during empiric tapering to QOD therapy suggest that a more objective approach is needed to maintain adequate immunosuppression while also attempting to avoid chronic steroid toxicity. These variations in the MEPN clearance and cortisol recovery may explain why aggressive steroid tapering is complicated by rejection episodes that occur in an unpredictable manner.

Erosive and generalized lichen planus responsive to azathioprine

Systemic corticosteroids are of value in severe lichen planus which interferes with the patient's life or is ulcerative or where there is nail destruction. Azathioprine has been shown to be effective steroid sparing treatment for generalized lichen planus. We report two patients with severe lichen planus who responded to azathioprine alone and suggest it may be an alternative therapy, especially when there are risk factors against corticosteroid use. Lichen planus accounts for approximately 1% of new presentations to a dermatology unit. It can affect all body areas and markedly interfere with a patient's life. Mucous membrane lesions are common (30-70%) but ulcerative lesions in the mouth are uncommon. Lichen planus seems to be immunologically mediated with evidence favouring a lymphocytotoxic process described in the literature. Treatment is mainly symptomatic and can be difficult. Systemic corticosteroids are of value in treating severe cases where the disease is interfering with a patient's life or when ulcerative mucous membrane lesions have occurred or if there is severe nail destruction. Relapse can occur on cessation of steroids. Azathioprine has been shown to be effective steroid sparing therapy for generalized lichen planus. However, the use of azathioprine alone has not been described. We report two cases of generalized, erosive lichen planus that responded well to azathioprine alone.

Chlorambucil—An effective corticosteroid-sparing therapy for pyoderma gangrenosum

A 21-year-old man, with a past history of severe aphthosis and arthritis between age 5 and 15 years, presented at age 18 years with a large leg ulceration, which developed after minor trauma. At that time he was otherwise healthy and taking no medications. Between 1983 and 1986 the patient failed to respond to intensive topical care to the ulcer, two attempted skin grafts, oral prednisone (up to 200 mg/day), sulfasalazine, dapsone (200 mg/day), multiple trials of intralesional triamcinolone acetonide, hyperbaric oxygen, azathioprine, methotrexate, clofazimine, minocycline, and three courses of pulse methylprednisolone therapy. Therapy with chlorambucil (4 mg/day) resulted in progressive improvement and complete healing with eventual cessation of all other therapy. The use of chlorambucil in pyoderma gangrenosum may be an effective adjunctive steroid-sparing therapy.